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Derivatives of celeboxib, use thereof and preparation thereof

a celeboxib and derivative technology, applied in the field of celeboxib derivatives, can solve the problems of limited clinical use, many chemotherapeutic drugs also produce undesirable side effects in patients, etc., and achieve the effect of reducing adverse side effects

Inactive Publication Date: 2014-06-19
GERMAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent relates to new derivatives of the drug celecoxib that have improved activity in treating cancer and inflammatory diseases. These derivatives lack the ability to inhibit COX-2 and COX-1 enzymes, which are associated with pain and inflammatory effects. Instead, these derivatives have been found to inhibit PDE5 and have an effect on neoplastic cell growth. The patent also includes methods for preparing these derivatives, as well as potential uses in treating pulmonary arterial hypertension and congestive heart failure.

Problems solved by technology

However, many chemotherapeutic drugs also produce undesirable side effects in the patient2,3.
Their clinical use, however, is limited by cardiovascular toxicities including myocardial infarction and stroke.
These toxicities result from COX-2 inhibition in endothelial cells and the suppression of prostacyclin, which has vasodilatory activity and can inhibit platelet aggregation.

Method used

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  • Derivatives of celeboxib, use thereof and preparation thereof
  • Derivatives of celeboxib, use thereof and preparation thereof
  • Derivatives of celeboxib, use thereof and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-(3-tert-Butyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (1)

[0052]Yield: 30% white powder; m.p.: 208.9° C.; TLC: Rf=0.78 (CH2Cl2:CH3OH, 5:1); 1H-NMR: δ 7.67 (d, J=9.01, Hz, 2H, ArH), 7.12 (d, J=8.73 Hz, 2H, ArH), 6.84-6.89 (m, 4H, ArH), 5.30 (dd, J=11.66, 5.00 Hz, 1H, H5), 3.70 (s, 3H, OCH3), 3.55 (dd, J=17.70, 11.70 Hz, 1H, H4b), 2.72 (dd, J=17.70, 5.04 Hz, 1H, H4a), 1.18 (s, 9H, tBu); 13C-NMR: δ 27.86, 33.55, 42.56, 55.00, 61.66, 111.34, 114.33, 118.87, 126.78, 130.70, 134.11, 147.83, 158.45, 161.46, 167.26; IR (cm−1): 2600-3200 (—OH), 1660 (—CO—); MS (ESI): 353.22 (M++1), 351.19 (M+−1) C21H24N2O3; Purity (HPLC): 96.2%

example 2

4-(3-tert-Butyl-5-(4-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (2)

[0053]Yield: 35% yellow powder; m.p.: 245.2° C.; TLC: Rf=0.81 (CH2Cl2:CH3OH, 5:1); 1H-NMR: δ 12.06 (brs, 1H, COOH), 8.06 (d, J=8.78, Hz, 2H, ArH), 7.54 (d, J=8.94 Hz, 2H, ArH), 7.32 (d, J=8.78 Hz, 2H, ArH), 6.70 (d, J=8.89 Hz, 2H, ArH), 5.42 (dd, J=11.88, 5.14 Hz, 1H, H5), 3.50 (dd, J=17.81, 11.93 Hz, 1H, H4b), 2.64 (dd, J=17.82, 5.15 Hz, 1H, H4a), 1.03 (s, 9H, tBu); 13C-NMR: δ 27.81, 33.58, 42.21, 61.56, 111.42, 119.51, 124.28, 127.06, 130.86, 146.85, 147.52, 149.64, 161.60, 167.16; IR (cm−1): 2600-3200 (—OH), 1678 (—CO—), 2966 (C—H); MS (ESI): 366.22 (M+−1) C20H21N3O4; Purity (HPLC): 99.81%

example 3

4-(3-tert-Butyl-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (3)

[0054]Yield: 50%; Yellow powder; m.p.: 235.4° C.; TLC: Rf=0.36 (CH2Cl2:CH3OH, 100:2); 1H-NMR: δ 8.11 (d, J=9.5 Hz, 2H), 7.67 (dd, J=16.8, 7.5 Hz, 4H), 6.89 (d, J=7.9 Hz, 2H), 5.60 (dd, J=11.52, 4.69 Hz, 1H), 3.65 (dd, J=17.9, 11.7 Hz, 1H), 2.84 (dd, J=17.99, 4.40 Hz, 1H), 1.19 (s, 9H); IR (cm−1): 2800-3200 (—OH), 1660 (—CO—); MS (ESI): 367.65 (M+) C20H21N3O4; Purity (HPLC): 97.6%.

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Abstract

Derivatives of celecoxib that lack cyclooxygenase inhibitory activity but have improved PDE5 inhibitory activity are provided along with pharmaceutical compositions containing them for the treatment or prevention of cancer. Such compounds are expected to have reduced toxicity compared with celecoxib and other cyclooxygenase inhibitors, and greater efficacy compared with conventional PDE5 inhibitors. Derivatives of celecoxib are also suitable for treating chronic inflammatory conditions, erectile dysfunction, pulmonary hypertension, congestive heart failure, and enhancement of cognitive function.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application claims the benefit under of U.S. Provisional Application Ser. No. 61 / 453,795, filed on Mar. 17, 2011 and entitled Derivatives of Celecoxib, Use Thereof and Preparations Thereof, the entire disclosure of which is incorporated herein by reference.TECHNICAL FIELD[0002]The present disclosure relates to certain derivatives of celecoxib. According to the present disclosure, the disclosed compounds lack COX-2 inhibitory activity but retain PDE5 inhibitory activity. The present disclosure also relates to pharmaceutical compositions comprising the disclosed derivatives of celecoxib, as well as a method of using the compounds for the treatment of cancer in a mammal. Also disclosed is a method for the preparation thereof. Disclosed derivatives of celecoxib are also suitable for treating chronic inflammatory conditions with reduced cardiovascular toxicity, erectile dysfunction, enhancement of cognitive functions, benign prosta...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D231/06
CPCC07D231/06C07D231/12
Inventor PIAZZA, GARY A.ABADI, ASHRAF H.
Owner GERMAN UNIV